Stroke is the third leading cause of human death in the US and a major health threat to our Veterans. According to a national survey, there are 1-2 stroke patients for every 1,000 Veterans. Unfortunately, so far there are very few effective therapies for stroke patients. Most previous and current experimental treatments for ischemic stroke have focused on affecting one signaling pathway, regulating an individual membrane protein/channel/receptor such as NMDA receptor or targeting one type of cell death mechanism such as apoptosis. The failure of many clinical trials using these approaches in recent years have generated the consensus that an effective therapy for complicated CNS disorders such as cerebral ischemia must have overwhelming protective effects on multiple pathways and multiple cell types. So far, there has been no therapy that is truly multifaceted and clinically feasible for acute stroke patients. One potential therapy, however, stands out for its versatile protective effects on the brain, heart and other organs: hypothermia therapy. Mild-to-moderate hypothermia has shown remarkable neuroprotective effects (up to 90% infarct reduction) against brain ischemia in animal and human studies. On the other hand, available cooling techniques of physical means are slow (3 hrs) and not practical, which have hampered clinical applications of hypothermia therapy to acute stroke patients. Thus, chemical compounds that can be utilized for hypothermia therapy have long been sought for clinical treatments. Using drug-induced hypothermia, it is expected that even a small drop of body temperature (1-2oC) should prevent the detrimental post-stroke hyperthermia, delay the evolution of ischemic injury, and thereafter extend the therapeutic window for other interventions. We have developed novel neurotensin derivatives such as ABS201 and ABS601 that can pass through the blood brain barrier to induce regulated hypothermia, reducing body and brain temperature by 3-5oC in 30 min without causing shivering. Systemic study, blood tests and autopsy examinations in rats and monkeys showed no toxic and adverse effects of these compounds. Post-ischemic administration of these compounds markedly attenuates ischemia-induced brain injury. These compounds thus provide a novel drug-induced hypothermia therapy. In this four year investigation, we will test two Specific Aims to focus on translational potential of the therapy. Aim 1 will determine the dose-response curves and time courses (cooling, maintaining and rewarming phases) of hypothermic NT/ABS compounds. A selected compound will then be examined for the novel approach of global brain protection against ischemic stroke. We will test the idea that drug-induced hypothermia suppresses multiple injurious mechanisms. As a result, it can block different types of cell death (apoptosis and necrosis) in different cells (neurons and non- neuronal cells) in gray and white matters. The treatment should also prevent disruption of the blood brain barrel, attenuate brain edema and hemorrhage. Aim 2 will evaluate structural integrity and long-term functional recovery of the ischemic brain, which is the ultimate goal of an effective therapy. Experiments will be performed in aging rats to mimic the most vulnerable population of Veterans; different ischemic stroke models will be tested in order to evaluate the therapy in a variety of clinical conditions. This research proposal is a result from several years of collaborative efforts in basic and preclinical investigations. It is expected that this research wll provide compelling evidence for developing a new category of global brain protection drugs and help to translate the chemical/pharmacological hypothermic therapy to clinical applications. PUBLIC HEALTH RELEVANCE: Narrative Ischemic stroke is the third leading cause of human death in the US and a major health threat to the aging population of Veterans. To develop a clinically effective and feasible therapy, we will test the brain protection and functional benefits induced by drug-induced hypothermia in stroke models of rodents using our novel neurotensin derivatives.